Project Summary Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal form of interstitial lung disease (ILD), affecting 100,000 per year in the US, with a 3-year survival rate of 50% and a large socio-economic healthcare burden. Early, accurate diagnosis is essential to determine treatment, which differs drastically between IPF and other ILDs. Initiating treatment as early as possible is a key strategy to prevent irreversible loss of lung function and maximize patient outcomes. Definitive IPF diagnosis can be made by CT in ~50% of cases when classic imaging features are present, which must include peripheral honeycombing. However, CT is unable to resolve features < 2 mm, including microscopic honeycombing present in ~50% of cases, which includes nearly all cases of early IPF. When CT fails to diagnose IPF, surgical lung biopsy (SLBX) is required to obtain tissue for microscopy, but has high morbidity and mortality risks. Evaluating therapeutic response is also critical for deciding which patients should stay on expensive, poorly-tolerated therapy and which should not. IPF microscopic features are indicators of disease progression, but cannot be assessed over time with either CT or SLBX. Our objective is to meet this critical need by clinically validating endobronchial optical coherence tomography (EB-OCT) for early microscopic IPF diagnosis and therapy response assessment. EB-OCT provides rapid 3D imaging with microscopic resolutions (< 10 ?m) well beyond CT capabilities. We have developed thin OCT catheters that can bronchoscopically access the subpleural lung, assessing 100x more lung volume at more distinct sites than SLBX without the associated risks. We have shown in a pilot study of 18 ILD patients that in vivo EB-OCT can detect microscopic honeycombing not visible with CT. Our data suggest that EB-OCT can differentiate IPF from non-IPF ILDs with near perfect accuracy as compared with SLBX. In order to validate this conclusively, we will conduct the proposed studies: In Aim 1, we will use our ex vivo EB-OCT and matched histology database to determine accuracy for IPF diagnosis ex vivo in an independent multi-reader, blinded assessment and validate automated methods to quantify individual IPF microscopic features known to indicate disease progression against histology. In Aim 2, we will translate these findings to a multi-centered prospective clinical study. We will determine the accuracy of EB-OCT for IPF diagnosis in patients with non-diagnostic CT undergoing diagnostic SLBX in an independent multi-reader, blinded assessment. We will then repeat EB-OCT in IPF patients, 6 months later, at the same locations and quantify EB-OCT features at each time point using the automated methods validated in Aim 1. We will compare EB-OCT changes amongst patients on and off therapy and against changes in lung function testing and survival. The accomplishment of these studies will eliminate a major obstacle in IPF by validating EB-OCT as a minimally-invasive, low-risk method for early, accurate diagnosis and assessment of therapy response. This will permit earlier therapy initiation, earlier assessment of efficacy, and increase survival for IPF patients.